Complete restoration of refractory mandibular osteoradionecrosis by prolonged treatment with a pentoxifylline-tocopherol-clodronate combination (PENTOCLO): a phase II trial.

PURPOSE: Osteoradionecrosis (ORN) is a nonhealing wound of the bone that is difficult to manage. Combined treatment with pentoxifylline and vitamin E reduces radiation-induced fibrosis and ORN with a good prognosis. We previously showed that the combination of pentoxifylline and vitamin E with clodronate (PENTOCLO) is useful in healing sternocostal and some mandibular ORN. Is PENTOCLO effective in ORN of poor prognosis? METHODS: 54 eligible patients previously irradiated for head and neck cancer (among 72 treated) a mean 5 years previously received exteriorized refractory mandibular ORN for 1.4 ± 1.8 years, mainly after local surgery and hyperbaric oxygen had been ineffective. The mean length of exposed bone (D) was 17 ± 8 mm as primary endpoint, and the mean Subjective, Objective, Management, and Analytic evaluation of injury (SOMA) score was 16 ± 4. Between August 2000 and August 2008, all patients were given daily oral PENTOCLO: 800 mg pentoxifylline, 1,000 IU vitamin E, and 1,600 mg clodronate 5 days per week alternating with 20 mg prednisone and 1,000 mg ciprofloxacin 2 days per week. The duration of treatment was related to consolidated healing. RESULTS: Prolonged treatment (16 ± 9 months) was safe and well tolerated. All patients improved, with an exponential progressive--(f[t] = a.exp(-b.t)--and significant (p < 0.0001) reduction of exposed bone (D), respectively (months): D(2) -42%, D(4) -62%, D(6) -77%, D(12) -92%, and D(18) -96%, combined with iterative spontaneous sequestrectomies in 36 patients. All patients experienced complete recovery in a median of 9 months. Clinical improvement was measured in terms of discontinuation of analgesics, new fracture, closed skin fistulae, and delayed radiologic improvement: SOMA(6) -64%, SOMA(12) -89%, and SOMA(30) -96%. CONCLUSION: Long-term PENTOCLO treatment is effective, safe, and curative for refractory ORN and induces mucosal and bone healing with significant symptom improvement. These findings will need to be confirmed in a randomized trial.

Current management for late normal tissue injury: radiation-induced fibrosis and necrosis.

Radiation-induced fibrosis (RIF) and radionecrosis (RN) are late complications that are usually considered irreversible. Usual management strategy includes eliminating local and general aggravating factors and controlling acute and chronic inflammation with steroids. Thanks to progress in understanding the pathophysiology of these lesions, several lines of treatment have been developed in clinical practice. However, results of clinical studies are difficult to compare because of variations in severity of RIF, method of RIF assessment, availability of efficient therapeutic drugs, treatment duration, and quality of trial design. For moderate established RIF, current management strategy mainly includes (1) anti-inflammatory treatment with corticosteroids or interferon gamma; (2) vascular therapy with pentoxifylline (PTX) or hyperbaric oxygen (HBO); and (3) antioxidant treatment with superoxide dismutase, tocopherol (vitamin E), and, most successfully, with a PTX-vitamin E combination. On the basis of etiology, RN can be managed by (1) anti-inflammatory treatment with corticosteroids and possibly clodronate, (2) vascular therapy with HBO and PTX, (3) antioxidant treatment with a PTX-vitamin E combination, and (4) a PTX-vitamin E-clodronate combination. Controlled randomized trials are now necessary to identify the best treatment at each step of RIF. In the future, these treatments of fibrosis and necrosis should include targeted drugs (such as growth factors) to take organ specificities into account.

The radiation-induced fibroatrophic process: therapeutic perspective via the antioxidant pathway.

The radiation-induced fibroatrophic process (RIF) constitutes a late, local and unavoidable sequela to high-dose radiotherapy, traditionally considered irreversible. Today, this process is partly reversible, thanks to recent progress in understanding the physiopathology of the lesions it causes and the results of recent clinical trials using antioxidant therapy. This review includes a synthetic description of the static and dynamic features of the RIF process, as reflected by its clinical, instrumental and histopathological characteristics, and by its cellular and molecular regulation. Schematically, three successive clinical and histopathological phases can be distinguished: a pre-fibrotic aspecific inflammatory phase, a constitutive fibrotic cellular phase, and a matrix densification and remodelling phase, possibly ending in terminal tissular necrosis. The respective roles of the chief actors in the RIF process are defined, as well as their development with time. A fibroblastic stromal hypothesis is suggested revolving around a 'gravitational effect' exerted by the couple ROS (reactive oxygen species)--fibroblasts, and partly mediated by TGF-beta1. A variety of strategies have been tested for the management of RIF. In the light of the mechanisms described, a curative procedure has been proposed via the antioxidant pathway. In particular, it was showed that superoxide dismutase and combined pentoxifylline-tocopherol treatment enables the process of established radiation-induced fibroatrophy to be greatly reduced or even reversed, both in clinical practice and animal experiments. The efficacy of combined pentoxifylline-tocopherol treatment in superficial RIF was confirmed in a randomised clinical trial, and then in successful phase II trials especially in uterine fibroatrophy and osteoradionecrosis. It is of critical importance to evaluate these new management approaches in larger clinical trials and to improve the recording of results for better outcome analysis. Mechanistic studies are always necessary to improve understanding of the RIF process and the antifibrotic drug action.